Total cholesterol, LDL-cholesterol, apolipoprotein-B, apolopoprotein-A1,
For years, the concentration of low-density lipoprotein (LDL-cholesterol) in blood serum has served as the go-to measure of cardiovascular disease risk. However, researchers have noted that LDL-cholesterol contains several constituents (small, dense vs. large, buoyant particles), which predict higher and lower risks for cardiovascular disease, respectively. More recently, researchers have proposed other measures of cardiovascular risk.
Apolipoprotein-B (apo-B) is a structural component of very-low-density lipoproteins, intermediate-density lipoproteins, and low-density lipoproteins. Each particle of these lipoproteins contains one molecule of apo-B. Thus, the blood plasma concentration of apo-B reflects total number of atherogenic (cardiovascular disease causing) particles in blood serum. Apolipoprotein-A1 is the major structural component of anti-atherogenic high-density lipoproteins (HDL), and the concentration of apo-A1 highly correlates with HDL levels. Apo-B and apo-A1 carry lipids (fats) into and out of arterial walls, respectively. To minimize risk of cardiovascular disease, we want our apo-B levels to be low and our apo-A1 levels to be high. The ratio of apo-B/apo-A1 represents the balance between atherogenic and anti-atherogenic particles and is a better predictor of cardiovascular risk than either apo-B or apo-A1 alone. A ratio of apo-B / apo-A1 of greater than 0.90 is considered high risk; 0.4 – 0.6 is better.
Apolipoprotein-A1
Cardiovascular diseases account for the largest share of US deaths annually. Thus, doctors and patients would like to know what readily measurable factor is the best predictor of cardiovascular mortality. The ratio of apolipoprotein-B (apo-B) to apolipoprotein-A1 (apo-A1) was found to the best predictor of cardiovascular deaths in younger people. Researchers in Sweden wondered apo-A1 or apo-B would be better predictors for older people than the ratio of apo-A1 to apo-B or the commonly used predictors, HDL-cholesterol and LDL-cholesterol. Research subjects participated in the Uppsala Longitudinal Study of Adult Men. The study began in 1970 when all men born between 1920 and 1924 and living in Uppsala were invited to participate. Blood samples came from 785 men with an average age of 77 years.
Over an average follow-up of five years, apo-A1 was the best predictor of death due to ischemic heart disease. Patients in the first, second, third, and fourth quartiles of apo-A1 concentration (ranked from low to high) has an absolute risk of death due to ischemic heart disease of 5.1%, 2.5%, 1.5%, and 0.5%, during follow-up. Apo-A1 facilitates binding of HDL-cholesterol to the cell surface. Higher concentration of apo-A1 presumably facilitates better physiological function of HDL-cholesterol.
Curiously, there was no significant relationship between in body-mass index, blood pressure, hemoglobin A1c, glucose, insulin, triglycerides, and high-sensitivity C-reactive protein for the men who died from ischemic heart disease and those who didn’t. Most of those factors are considered to be risk factors for cardiovascular disease.
Ratio of apo-B to apo-A1
Researchers in the UK investigated the inter-relationships among apolipoprotein-B, apolipoprotein-A1, LDL-cholesterol, and HDL-cholesterol. The case-control study subjects included 3,510 patients with acute myocardial infarction (heart attack) and 9,805 controls. Relative risks of myocardial infarction were more strongly linked to apo-B than to LDL-cholesterol. After controlling for apo-B levels, relative risks were more strongly negatively linked to apo-A1 than to HDL-cholesterol. In addition, the ratio of apo-B/apo-A1 provided substantially more information about myocardial infarction risk than other commonly used measures including the ratio of LDL-cholesterol/HDL-cholesterol, or the ratio of total cholesterol/HDL-cholesterol, or non-HDL-cholesterol, or total cholesterol.
Support for the usefulness of the apo-B / apo-A1 ratio
Swedish researcher Goran Walldius reviewed the literature that summarized the benefits of using the apo-B/apo-A1 ratio as the preferred measure of cardiovascular risk compared to other measures such as LDL-cholesterol or the ratio of total cholesterol/HDL-cholesterol. He cites the following benefits: 1) standardized analytical technique, 2) no need for a fasting blood sample, 3) no need to account for high levels of triglycerides, 4) intuitive meaning of the apo-B/apo-A1 ratio as the balance of "bad" and "good", 5) strong associations with atherosclerosis, abdominal obesity, and type 2 diabetes, and 6) reasonable cost to analyze samples.
Researchers in Russia and Norway used data from 157 men (average age 36 years) with normal levels of blood lipids (fats). The average ratio of apo-B/apo-A1 for these men was 0.52, well in the healthy range. But 30 men who had ratios more than 0.9 had higher atherogenic index of plasma due to higher levels of triglyceride. Even adults with normal blood fats can have an unhealthy apo-B/apo-A1 ratio.
Researchers in China used data from 2,256 Han Chinese patients who underwent a percutaneous coronary heart disease intervention to evaluate the effectiveness of three predictors of coronary heart disease. Cross-sectional data showed that the odds of coronary heart disease severity increased significantly across increasing quartiles of the apo-B/apo-A1 ratio. After adjusting for conventional risk factors, longitudinal data for 1,639 patients showed that the risk of developing coronary heart disease outcomes increased significantly after 5 years of follow-up across increasing quartiles of the apo-B/apo-A1 ratio and for the Framingham Risk Score. But the apo-B/apo-A1 ratio was a stronger predictor that the Framingham Risk Score. The ratio of total cholesterol/HDL-cholesterol did not significantly predict risk of developing coronary heart disease outcomes. Overall, the apo-B/apo-A1 ratio was the best predictor of coronary disease prevalence and incidence.
Ratio of total cholesterol to LDL-cholesterol
A team of researchers in the UK used data from 346,686 participants without cardiovascular disease at baseline in the UK Biobank to compare the predictive ability of conventional lipoprotein and apolipoprotein measures of cardiovascular disease risk. Data from a subset of 68,649 participants taking a statin but without cardiovascular disease at baseline provided another test of predictive ability. Apo-B, LDL-cholesterol, and non-HDL-cholesterol were high correlated with each other, while ApoA1 and HDL-cholesterol were highly correlated with each other. Each 1 standard deviation increase in Apo-B, directly measured LDL-cholesterol, and non-HDL-cholesterol predicted nearly identical significant increased risks of incident cardiovascular events (23, 20, 21, respectively) during a median follow-up of 9 years. When total cholesterol and HDL-cholesterol were included in a statistical model, the addition of apo-B or LDL-cholesterol did not improve predictive ability for cardiovascular disease events. The authors concluded that total cholesterol and HDL-cholesterol measured in a non-fasted state adequately predicted cardiovascular disease risk. Their data suggested that the ratio of apo-B/apo-A1 also adequately predicted cardiovascular disease risk.
An accompanying editorial supported the conclusions of the team of UK researchers, with the proviso that data for apolipoprotein-B can provide additional information for patients with multiple cardiovascular risk factors. The editorial also noted that the lipid data used by Welsh and others came from non-fasting blood samples. Thus, the editorial supported the current status-quo of using the ratio of total cholesterol/HDL-cholesterol as the best measure of cardiovascular risk for most patients.
What to do
Ask your primary medical care provider for a blood draw so you can better understand your cardiovascular disease risk. Make sure you request tests for total cholesterol, LDL-cholesterol, HDL-cholesterol, apo-B, and apo-A1. You test results will likely also show the ratios of total cholesterol/HDL-cholesterol and apo-B/apo-A1. Your medical car provider can help you interpret the test results.
